There is a pressing need for appropriate animal models to screen promising new antivirals, assess the suitability of future chemotherapeutic targets, and compare different drugs and chemotherapeutic approaches in their ability to alter the course of lentivirus induced CNS disease. From the initial studies of this Center and the work of other investigators, the FIV/cat system has been developed into a legitimate model for the study of lentivirus pathogenesis of the CNS. Not only does FIV produce a disease that is very similar to human AIDS, but it is also similar to HIV at both the molecular and biochemical levels. In our Center, numerous parameters have been established to monitor the effects of virus infection on the CNS. We now want to expand these studies to investigate the effects of therapeutic agents on neurologic aspects of the disease. Additionally, we will examine the important therapeutic problem of virus resistance as well a mechanisms the virus uses to escape the effects of therapeutic agents. In this proposed project, we plan to specifically examine the effects of promising anti-TNF-alpha agents, the therapeutic outcome of NMDA receptor antagonists, the efficacy of new antiviral agents, and the effects of combined therapeutic agents on FIV induced neurological disease, as well as monitor for the development of drug-resistant mutants and map the genetic determinants associated with the resistant phenotype. Our long-term objective is to develop the FIV/cat system into a predictive animal model for assessing the effects of therapeutic compounds on the neurologic aspects of lentivirus diseases. It is important to examine not only how the therapeutic agent affects the neurologic form of the disease but also how the virus changes in response to the presence of the drug. In this set of proposed studies, we will examine new therapeutic approaches as well as the role antiviral resistant mutants play in lentivirus pathogenesis, enhancing our understanding of the interactions that occur among the lentivirus, host, and therapeutic agents. It is now time to use this system to gain insight into disease mechanisms as well as examine potential therapeutic approaches that ultimately may be used in human AIDS patients, as part of the Mitler/Darko Component of this Center.